Phenothiazine derivatives and their preparation



United States Patent 3,084,162 PHENOTHIAZINE DERlVATIVES AND THEKR PREPARATION Martin A. Davis, Montreal, Quebec, Canada, assignor to American Home Products Corporation, New York, N.Y., a corporation of Delaware No Drawing. Filed Dec. 12, 1961, Ser. No. 158,871 Claims. (Cl. 260-243) This invention relates to certain new chemical compounds, derivatives of phenothiazine, which have pharmacological activity, being active spasmolytic agents and as long-active antitussive agents.

This application is a continuation-impart of my copending application, Serial No. 71,172, filed November 23, 1960, which, in turn, is a continuation-in-part of my copending application, Serial No. 35,444, filed June 13, 1960, both now abandoned.

My new chemical compounds are characterized by high anti-spasmotic activity against acetylcholine and barium chloride, accompanied by toxicity of only a very low order. Such compounds, possessing spasmolytic activity of the papaverine-like type, are useful as therapeutic agents in treating spasms, such as those of the bladder or intestinal tract.

More particularly, my invention is directed to the novel chemical compounds Z-(M-piperideinoethoxy)-cthyl phenothiazine-lO-carboxylate and 2-(4-ethyl-A -piperidcinoethoxy)-ethyl phenothiazine-lO-carboxylate and their pharmacologically active salts, particularly the hydrohalide salts.

In alternative nomenclature, 2-(4-ethyl-A -piperideinoethoxy)-ethyl phenothiazine-l0-carboxylate may also be designated as 2 [(4-ethyl l,2,5,6-tetrahydropyridino) ethoxyl-ethyl phenothiazine-lO-carboxylate.

One of the compounds coming within the scope of my invention, the compound 2-(M-piperideinoethoxy)ethyl phenothiazine-lO-carboxylate, is characterized by twice the spasmolytic activity against acetylchoiine, and almost twice the spasmolytic activity against barium chloride, as the somewhat related compound Z-piperidinoethoxyethyl phenothiazinc-lOcarboXyIate, both compounds being compared as the bases. These comparative values are determined by the standard method of R. Mag nus, with guinea pig ileum strips as the test object, using acetylcholine and barium chloride as spasmogens.

When compared on a toxicity basis, Z-(M-piperideinoethoxy)ethyl phenothiazine-lO-carboxylate has only ap proximately half the toxicity as 2-piperidinocthoxyethylphenothiazine-IO-carboxylate. This low toxicity, coupled with high activity, which is typical of the compounds of my invention, renders those products of interest both as spasmolytic agents and as antitussive agents.

My invention is also directed to the preparation of the novel compounds from readily available starting materials.

ln base form my novel chemical compounds, possessing pharmacological activity, particularly as long-acting antitussive agents, may be represented by the following formula:

C| OO.CHz.CC:-0.CIT2.CH3N\ R wherein R represents hydrogen or ethyl.

As utilized therapeutically, it is preferable that these compounds be employed in the form of their acid addition salts with pharmaceutically acceptable acids. Among such salts are the hydrohalide salts, particularly the hy- 3,084,162 Patented Apr. 2, 1963 "ice drochlorides. These salts possess the long-acting antitussive properties characteristic of the bases.

The new compounds may be readily prepared starting with a known compound such as 1,2,5,6-tetrahydropyridine or a homolog thereof such as 4-ethyl-l,2,5,6-tetrahydropyridine. In my preferred process the compound selected is reacted with 2-(chloroethoxy)ethanol and the resulting compound further reacted with a derivative of phenothiazine-IO-carboxylic acid chloride. Details of the procedure are given in the following illustrative examples.

Example I A mixture of 16.6 grams (0.2 mol.) of .M-piperideine (1.2,5,o-tetrahydropyridine) and 12.4 grams (0.1 mol.) of 2-chloroethoxyethanol was heated on a steam bath for twelve hours, during which time a bulky precipitate formed. The reaction mixture was then dissolved in water and the resulting solution saturated with solid sodium hydroxide. This resulted in the separation of an oil which was taken up in benzene, the organic phase thereof dried, and the dried oil distilled in vacuo, i.e., at a pressure less than atmospheric, to give 10.1 grams of 2(A piperideinoethoxy)-ethanol. The product boiled at C. at 0.06 millimeter of mercury pressure; r2 1.4870.

This compound was then converted to its hydrochloride salt by the addition of gaseous hydrogen chloride in ether solution and the hydrochloride salt recrystallized from isopropanol-ether. The resulting compound melted at lll112 C. (with decomposition). Analysis confirmed the empiric formula C H NO Cl.

in an alternate procedure the first reaction, as described above, was carried out with the reagents, to, A -piperideinc and Z-chloroethoxycthanol, suspended in 50 milliliters of boiling benzene. The reaction mixture was heated at the boiling point of benzene for 23 hours, whereupon a somewhat higher yield of Z-(fi-piperideinoethoxyyethanol was obtained.

Example 2 The alcohol prepared in accordance with Example 1, Z-(fipiperideinoethoxy)-ethanol, in the amount of 8.5 grams (0.05 mol.), was dissolved in a little dry pyridine and the resulting solution added, with stirring, to a suspension of 13.1 grams (0.05 mol.) of phenothiazine-lO- carboxylic acid chloride in 20 milliliters of pyridine. The mixture was stirred for one hour at room temperature, and this was followed by heating for one hour on a steam bath.

The solution was then cooled, added to ice water, and made alkaline by the addition of sodium carbonate. This resulted in the precipitation of a gum which was washed repeatedly with water, taken up in benzene, and again washed with water. Drying the resulting solution and evaporation left 17.0 grams of a dark oil. On .trituration with hot hexane this yielded the desired base, 2-(n -piperideinoethoxy)-ethyl phenothiazine-lOcarboxylate, as a. light-colored oil.

The hydrochloride salt of the new base was prepared by dissolving the free base in ether, adding thereto a small molar excess of a solution of hydrogen chloride in ether, and filtering off the resulting precipitate. This compound was Z-(N-piperideinoethoxy)-cthyl phcnothiazine-IO- carboxylate hydrochloride. On recrystallization from ethanol-ether, or from acetone, it was found to exist in two crystalline forms, melting at l36138 C. and at 159 161 C. Analysis confirmed the empiric formula CggHggNgOsS.

Example 3 4-ethyl-l,2,5,6-tetrahydropyridine was prepared by the 3 reduction of 4-ethylpyridine with sodium in butanol, as described by Wawzonek et al. [J.A.C.S. 74, 2894 (1952)]. Careful fractional distillation through a small column packed with Dixon gauze rings gave a fraction of boiling point 157-1605 C.; n l.46421.471l. The yield was 35 percent.

Example 4 The compound prepared as described above, 4-ethyl- 1,2,5,6-tetrahydropyridine, in the amount of 14.3 grams (0.13 mol.), 16.1 grams (0.13 mol.) of 2-(chloroethoxy)- ethanol and 20.2 grams (0.2 mol.) of triethylamine were introduced into 100 milliliters of dry toluene, and the mixture heated under reflux for 18 hours.

The precipitate, which had deposited on cooling, was filtered off, and the filtrate was evaporated and dissolved in water. The solution was then made alkaline by the addition of an excess of solid sodium hydroxide, and the resulting oil was taken up in benzene and distilled. There was thus obtained a fraction consisting of 8.2 grams having a boiling point of 93 C. at 0.1 millimeter of mercury pressure; n 1.4805. This consisted of 2- [(4-ethyl-l,2,5,6-tetrahydropyridino)ethoxy]ethanol.

The oxalate salt of 2-[(4-ethyl-l,2,5,6-tetrahydropyridino)ethoxy]ethanol was obtained by adding the compound to a solution of an excess of oxalic acid dissolved in acetone-ether. The compound as recrystallized from isopropanol had a melting point of 75-76 C.

Analysis confirmed the empiric formula C H NO Calculated: C, 53.96; H, 8.01; N, 4.84. Found: C, 54.23; H, 7.82;N, 4.75, 4.79.

Example The basic alcohol prepared as described in Example 4 was added dropwise in the amount of 7.45 grams (0.037 mol.) to a suspension of 9.76 grams (0.037 mol.) of phenothiazine-IO-carboxylic acid chloride in 20 milliliters of dry pyridine. The mixture was then stirred for one hour at room temperature, followed by heating at 85 C. for forty minutes.

The cooled mixture was then poured into ice water and the mixture made alkaline with sodium carbonate. The resulting gum was washed repeatedly with water, taken up in benzene and washed with further portions of water. Evaporation of the benzene gave 15 grams (94.5

4 percent yield) of crude 2-[(i-ethyl-1,2,5,6-tetrahydropyridino)ethoxy]ethy1 phenothiazine 10 carboxylate, which may also be designated as 2-(4-ethyl-A -piperideinoethoxy)-ethyl phenothiazine-l0-carboxylate. The dark oil was triturated with hot hexane, evaporation of which gave 12.4 grams of a lighter colored product. The hydrochloride was recrystallized from acetone-isopropanolether and had a melting point of 159160 C.

Analysis confirmed the empiric formula Calculated: C, 62.53; H, 6.34; S, 6.96; C], 7.69.

Found: C, 62.36; H, 6.36; S, 7.00, 6.96; Cl, 7.74, 7.67.

I claim:

1. A compound selected from the group which consists of a compound of the formula:

coo.crracnioonionwbi 42 References Cited in the file of this patent UNITED STATES PATENTS 2,778,824 Von Seemann Jan. 22, 1957 2,885,404 Petrow et al. May 5, 1959 2,952,685 Najer et a1 Sept. 13, 1960 2,989,529 Schuler June 20, 1961 OTHER REFERENCES Chappell et al.: Canadian J. Biochemistry and Physiol,

volume 36, pages 47581 (1958). 

1. A COMPOUND SELECTED FROM THE GROUP WHICH CONSISTS OF A COMPOUND OF THE FORMULA: 